Small Molecule Drug C381 Attenuates Brain Vascular Damage Following Repetitive Mild Traumatic Injury.

Autor:	Li L; Palo Alto Veterans Institute for Research, VA Palo Alto Health Care System, Palo Alto, California, USA., Nguyen A; Palo Alto Veterans Institute for Research, VA Palo Alto Health Care System, Palo Alto, California, USA., Zhao B; Palo Alto Veterans Institute for Research, VA Palo Alto Health Care System, Palo Alto, California, USA., Vest R; Department of Chemical Engineering, Stanford University, Stanford, California, USA., Yerra L; Palo Alto Veterans Institute for Research, VA Palo Alto Health Care System, Palo Alto, California, USA., Sun B; Palo Alto Veterans Institute for Research, VA Palo Alto Health Care System, Palo Alto, California, USA., Luo J; Palo Alto Veterans Institute for Research, VA Palo Alto Health Care System, Palo Alto, California, USA.; Polytrauma System of Care, VA Palo Alto Health Care System, Palo Alto, California, USA.
Jazyk:	angličtina
Zdroj:	Neurotrauma reports [Neurotrauma Rep] 2024 Oct 22; Vol. 5 (1), pp. 1016-1026. Date of Electronic Publication: 2024 Oct 22 (Print Publication: 2024).
DOI:	10.1089/neur.2024.0060
Abstrakt:	Traumatic brain injury (TBI) remains a significant public health concern, with no effective therapeutic interventions to ameliorate the enduring consequences. The prevailing understanding of TBI pathophysiology indicates a central role for vascular dysfunction. Transforming growth factor-β (TGF-β) is a multifunctional cytokine crucial for vascular development. Aberrant TGF-β signaling is implicated in vascular pathologies associated with various neurological conditions. We recently developed a novel small molecule drug, C381, a TGF-β activator with the ability to restore lysosomal function. Here we used a mouse model of repetitive mild TBI (mTBI) to examine whether C381 would attenuate vascular injury. We first employed RNA-seq analysis to investigate the gene expression patterns associated with mTBI and evaluated the therapeutic potential of C381 in mitigating these changes. Our results demonstrate distinct mTBI-related gene expression signatures, prominently implicating pathways related to vascular integrity and endothelial function. Notably, treatment with C381 reversed these mTBI-induced gene expression changes. Immunohistochemical analysis further corroborated these findings, revealing that C381 treatment attenuated vascular damage in mTBI-affected brain tissue. These findings strongly support the potential clinical usefulness of C381 as a novel therapeutic intervention for mTBI. (© The Author(s) 2024. Published by Mary Ann Liebert, Inc.)
Databáze:	MEDLINE
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